Leptin regulates food intake and body weight by acting in the brain. Leptin normally inhibits food intake and causes weight loss, however, most obese subjects are hyperleptinemic and leptin resistant. The etiology of leptin resistance is unknown, but changes in signaling downstream of the leptin receptor in neurons may play a role. Recently phosphatidylinositol 3-kinase (PI3K) was implicated in mediating leptin's affects on energy homeostasis; however it's unknown if changes in this pathway contribute to, or are effected by, the development of leptin resistance. Transgenic and gene therapy techniques were used to create mice in which dynamic regulation of PI3K using 2-photon microscopy can be monitored in neurons. This technology will be used to determine if leptin activation of PI3K is decreased in obese, leptin resistant mice. If PI3K activity is decreased in obese mice the contributions of the Stat3 and PI3K pathways in leptin resistance will be studied. Additionally, as an extension of the imaging approach, and to further develop the technology for studying neuronal control of energy balance, I will generate a transgenic mouse that conditionally expresses a neuronal activity reporter. [unreadable] [unreadable]